Psoriasis is a relatively common skin disorder with an incidence that ranges from 0.5% to 3% in different populations. The lowest incidence is seen in North American Indians, and the highest in caucasians of Scandinavian countries. The disease is distinct from other dermatoses associated with epidermal hyperplasia such as ichthyosis, in that inflammatory cell accumulation is a prominent histological feature of psoriasis. The cause of psoriasis is unknown but the disease has a strong genetic component with approximately one-third of patients having affected relatives.
Multiple humoral and immune factors have been implicated in the development of psoriasis. Several of these factors are leucotrienes (IL2, IL3, IL6), some are growth factors TGF-.alpha.) and some are other cytokines (.gamma.-interferon). Additionally, increased keratinocyte proliferation, perivascular inflammation of the dermis, neutrophil migration into the epidermis, and increased production of cytokines such as interleukins IL-1 and IL-8 are commonly seen in psoriatic lesions. The lesions exhibit increased expression of molecules such as intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which influence lymphocyte and neutrophil migration and retention in the affected skin.
Current hypotheses of the pathogenesis of psoriasis propose that T cell recruitment to the skin endothelium is an initiating event in the development of psoriasis. Release of interferon gamma (IFN-.gamma.) and tumor necrosis factor-.alpha. (TNF-.alpha.) by activated T cells and macrophages leads to enhanced expression of cellular adhesion molecules on the endothelium (ICAM-1) permitting retention of such activated T cells in the region of the dermal capillaries. Continued production of IFN-.gamma., as well as other leucotrienes such as IL-6 and IL-8 transforms normal keratinocytes (KC) to express an increased number of receptors for ICAM-1, and produce enhanced amounts of transforming growth factor-.alpha. (TGF-.alpha.). Continued production of TGF-.alpha. by keratinocytes is associated with decreased negative feedback effects of IFN-.gamma. on TGF-.alpha. production which is linked to markedly decreased expression of type II histocompatibility antigen (HLA-DR) on the keratinocytes. This in turn is associated with less growth inhibition and development of the psoriatic plaque.
Methotrexate, etretinate, and more recently cyclosporine have been used in the treatment of psoriasis. All these agents have significant side effects and some are only effective in specific forms of psoriasis. Etretinate, for example, is most effective in erythrodermic and pustular psoriasis but is not effective in chronic plaque psoriasis. Its use is further restricted to males and females beyond their reproductive years. The use of the immunosuppressive agents methotrexate and cyclosporine can potentially result in severe toxic reactions.
Autoimmune disease is any of a large group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents. Such disorders may be systemic or organ specific. Rheumatic disease, a type of autoimmune disease, is any of a variety of disorders characterized by inflammation, degeneration, or metabolic derangement of the connective tissue structures of the body. Transplant rejection is an immune reaction seen in patients having received an organ or tissue graft from another individual.
Methotrexate and cyclosporine are also administered in the treatment of rheumatoid arthritis. Another immunosuppressant, azathioprine, is used in the treatment of rheumatoid arthritis and organ transplant rejection. Use of these immunosuppressants results in the risk of severe bone marrow depression and severe toxic reactions.
Accordingly, there is an urgent need for development and identification of relatively non-toxic agents that are effective in the treatment of patients with psoriasis, rheumatoid disease, autoimmune disease, and transplant rejection.
The anti-thyroid thioureylenes, which include propylthiouracil, methimazole, and carbimazole, are often used as first line treatment for patients with hyperthyroidism. Another thioureylene, methylthiouracil, has also been used in the past as an anti-thyroid compound. In developing countries, they are generally the only agents used to treat patients with hyperthyroidism, and have been used continuously for this purpose for decades. The principal effect of these drugs is to impair thyroid hormone biosynthesis and restore thyroid hormone levels to the euthyroid range.
In addition to their effects on thyroid hormone biosynthesis, this class of drugs has been shown to exhibit immune modulatory effects. In in vitro studies using peripheral blood lymphocytes (PBL), propylthiouracil (2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone, PTU), and the related thioureylene methimazole (2-mercapto 1-methylimidazole, MMI), were shown to decrease IgM and IgG production and decrease the activity of immunoglobulin-secreting cells in plaque forming assays. MMI is also known to augment natural killer cell (NK) activity. Peripheral blood lymphocytes obtained from patients with Graves' disease, believed to be an autoimmune disorder, when cultured in the presence of PTU and MMI showed a significantly increased percentage of total and suppressor/cytotoxic cells and reduced activated lymphocytes when compared to non-PTU and non-MMI treated PBL. In addition, thioureylenes act as free radical scavengers.
The incidence of side effects from PTU and MMI as currently used is very low. The most serious side effect is agranulocytosis with a maximal incidence of 1 in 500. There is very little difference in the incidence of this side effect between the two thioureylenes. If the drug is discontinued, recovery is the rule.
The most common drug-related side effect is the development of a mild, sometimes purpuric, papular rash. The rash often subsides without interrupting treatment. Other less frequent side effects consist of pain and stiffness in the joints, paresthesia, headaches, nausea, and loss or depigmentation of the hair. Drug fever, hepatitis and nephritis are extremely rare.
Thiabendazole, (2-(4-thiazolyl)-1H-benzimidazole) an anthelmintic used to treat patients with parasitic infections, is closely related in chemical structure to the thioureylenes. The precise mode of action of thiabendazole on parasites is unknown. Common side effects associated with thiabendazole therapy include gastrointestinal disturbances such as nausea, vomiting, anorexia, and diarrhea. Central nervous system side effects such as dizziness, weariness and drowsiness frequently occur. Erythema multiforme, a condition characterized by vivid red lesions of the skin of the face, neck, forearms, legs and dorsal surfaces of the hands and feet, has also been associated with thiabendazole therapy.
Thus, the thioureylenes and thiabendazole are relatively non-toxic agents which have been used in various therapies for years and whose side effects are well known. There is a need to develop new uses for these drugs, especially for the treatment of conditions such as psoriasis and autoimmune disorders where no satisfactory therapy has yet been developed.